This project tests specific hypotheses about functional and structural brain abnormalities in patients with Persistent Lyme Encephalopathy (PLE) and it cvaluates the efficacy of 10 weeks of IV ceftriaxone among patients previously treated with shorter courses of Iv antibiotics. Prior planar rCBF and SPECT studies of PLE reveal diffuse deficits affecting cortical and subcortical areas, primarily the white matter. These scans are often interpreted as consistent with vasculitis, multi-infarct dementia, or Lyme Disease. MRI series demonstrate that between 20-400/o of patients have hyperintensities, suggestive of inadequate arteriolar perftision resulting in demyelination and gliosis. To understand better the significance of these imaging abnormalities, this project will employ MRI and PET imaging and cognitive testing: a) to examine whether the functional imaging deficits are primarily vascular or metabolic in nature; b) to evaluate whether time course of improvement in MRI and PET scans correlates with clinical cognitive improvement; c) to identify whether deficits in blood flow (CBF), cerebral metabolism (CMR), and extent of MRI hyperintensities have prognostic significance; and d) to determine whether a subgroup of patients with poor outcome PLE have impaired vascular reserve 60 patients with PLE and 20 matched controls will be studied over 4 years. A second major goal is to determine the efficacy of a 10 week placebo-controlled trial of IV ceftriaxone in PLE using objective behavioral and imaging measures. After treatment, patients will be monitored off antibiotics to week 24. Durability of response will be examined by cognitive retesting at wk 48. Imaging procedures include MRI (T1 sagittal, 3D volumetric, T2 spin echo, FLAIR, and magnetization transfer sequences), O15. H2O PET during rest and hypercapnia, and FDG PET assessment of resting rCMR. We will test specific hypotheses about reversible and fixed functional and structural abnormalities that may account for antibiotic responsive and -unresponsive PLE. These hypotheses derive from histopathological studies indicating that a subgroup of patients with PLE have evidence of a vasculitic process that may lead to a syphilis-like endarteritis obliterans, with impairment in hcmodynamic reserve. This study will enhance our understanding of the pathophysiology and treatment of patients suffering with the disabling effects of persistent Lyme encephalopathy.